Pulmonary Valved Graft with Regeneration Potential for Pediatric Patients

Congenital heart diseases (CHD) refer to abnormalities present in the heart and the great vessels at birth. CHD is the most commonly diagnosed birth defect and the leading cause of birth-related mortality. These abnormalities can be a single defect or a combination of multiple defects that can alter the blood flow to and/or from the heart to the body. CHD affects approximately 40,000 newborns annually in the US and 1.35 million globally. The prevalence of CHD in the US population has been estimated to be close to 2.9 million patients, which represents about 25% of the total number of CHD cases worldwide. Among patients with CHD, around 22% of the total critical CHDs are affected by anomalies that impact the right ventricular outflow tract (RVOT), such as tetralogy of Fallot (ToF), pulmonary atresia, truncus arteriosus, and transposition of the great vessels. Replacement valves and conduits are needed to replace structures that are congenitally absent or hypoplastic in these conditions and restore normal blood flow. The choice of materials for RVOT reconstruction in CHD patients remains a controversial and inadequate area of study. Although glutaraldehyde-fixed bovine jugular vein (BJV) (Contegra) is a commonly used material due to its unlimited availability and lack of antigenic reaction, complications such as stenosis at the distal anastomosis of the conduit, aneurysm, or pseudoaneurysm have been reported in 6-50% of patients, with an increased risk of infection after implantation. The glutaraldehyde crosslinking process results in a stiff and calcification-prone tissue material, leading to early failure of the bioprosthetic device. Recent studies have highlighted that the early failure of bioprosthetic valves may not only be attributed to calcification but also to non-calcification mechanisms such as accumulation of advanced glycation end products (AGEs), altered collagen microstructure, and elevated tissue crosslinking. Glutaraldehyde treatment also prevents cellular repopulation of the tissues, making them incapable of cell-mediated remodeling and leading to the accumulation of AGE-related products. Pediatric patients with a higher metabolism have a higher risk of structural valve failure, which results in multiple re-operations throughout their lifetime. There is, therefore, an urgent need to develop more durable pulmonary valved grafts that are resistant to calcification, inflammation, thrombosis, and accumulation of AGEs, and that have regenerative potential, as a safe reconstructive device for pediatric patients. We propose to develop a pulmonary valved graft (PVG) from a decellularized and pentagalloyl glucose (PGG) treated (Also referred to as TxGuardTM) bovine jugular vein. TxGuardTM PVG will be non-thrombogenic, infection- and calcification-resistant, prevent accumulation of AGEs, and have a potential to remodel and grow. Based on reproducible pre-clinical data during STTR Phase 1 and SBIR Phase II, we firmly believe that the new device would provide an improved option for millions of patients than what is currently available. Proposed specific aims for SBIR Phase IIB are: Aim 1: Design freeze of TxGuardTM PVG for final testing for FDA submission. Sub-aim 1.1 - Optimizing and validating sterilization for TxGuardTM PVG. Sub-aim 1.2 - Optimizing and validating packaging and storage for TxGuardTM PVG. Aim 2: Evaluate GMP grade TxGuardTM PVG for material biocompatibility as per the ISO 10993 standards for permanent (>30 days) blood/ tissue contact device. Aim 3: Test the final TxGuardTM PVG device for function in vitro and in vivo for FDA submission. Sub-aim 3.1 - Hydrodynamic performance (steady flow pressure drop, steady backflow leakage, pulsatile flow pressure drop, pulsatile flow regurgitation) for different conduit sizes and accelerated wear testing (AWT) for three different sizes. Sub-aim 3.2 - Perform extended (140 days) GLP pre-clinical in-vivo testing for TxGuardTM PVG (n=6) in growing lambs and compared to the clinically available Contegra BJV or equivalent conduits (n=3). The outcome of these studies will be used for the FDA submission for the new device approval following the Humanitarian Device Exemption (HDE) guidelines. Confidential Page 1 of 1